Local conditions and cellular interactions at the site of injury determine whether repair or regeneration of the damaged tissues will occur following injury. The long-term objectives of this investigation are to (l) define the conditions that select and promote regeneration, (2) understand the means through which these factors exert their influence, and (3) acquire greater understanding of the regulation of skeletal muscle development and regeneration. This information will lead to identffication or development of clinical interventions that (a) will produce more efficient and more complete functional restoration of damaged tissues or organs following injury and (b) amelioration or correction of deficits arising from disorders in muscle development. This investigation will explore the following central hypothesis: Regeneration is an adaptive response to injury that requires (a) selective activation and mobilization of parenchymal cells and (b) continued cellular dialogs and interactions to ensure effective integration of these responding cells into the damaged parent tissue or organ. The immediate objectives of the present investigation are: (l) to define potential regulatory factors that are uniquely associated with regenerating skeletal muscle, (2) to identify conditions that lead to skeletal muscle regeneration, (3) to define interactions among effector cells that favor regeneration as a resolution to skeletal muscle injury, and (4) to assign roles to the inflammatory response and physical substrate in promoting skeletal muscle regeneration. Minced muscle will serve as the regeneration model, while killed (freeze/thaw) minced muscle and polyvinyl alcohol sponges will serve as repair models. Differential expression and production of regulatory factors (e.g., growth factors) will be determined using molecular biological techniques (polymerase chain reaction, RNase protection assays and possibly RNA differential display) and immunoassays. Effects of wound fluids and extracts from regenerating muscle will be assessed on fibroblasts, macrophages, and myogenic cells in culture. In addition, interactions among these cells will be assessed in culture either through use of conditioned media or coculture. Proliferation, extracellular matrix production, growth factor expression and production, and changes in phenotypic expression associated with myogenesis will be evaluated using incorporation of labeled precursors, immunoassays, biochemical, and immunohistological methods. The roles of inflammation will be explored by manipulating inflammatory responses (by irradiation, use of neutralizing antibodies, or introduction of inflammatory cells), by inoculation of myogenic cells (alone or in combination with fibroblasts and/or macrophages) into implanted polyvinyl alcohol sponges, viable minced muscle, or killed minced muscle. Conditions that are compatible with (or permissive for) regeneration will be discriminated from those that are potential regulators of regeneration.